HMGB1 Protects the Heart Against Ischemia–Reperfusion Injury via PI3K/AkT Pathway-Mediated Upregulation of VEGF Expression

Abstract

Delivery of exogenous high mobility group box 1 (HMGB1) may exert a beneficial effect on myocardial ischemia-reperfusion (I/R) injury. Since the expression of vascular endothelial growth factor (VEGF) and phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) in the myocardium mediates the cardioprotective function of basic fibroblast growth factor, we hypothesized that VEGF and the PI3K/Akt signaling pathway also mediate the protective effects of intravenously delivered HMGB1. Thus, the objective of the present study was to analyze the impact of intravenous administration of HMGB1 on the myocardial expression of VEGF, myocardial fibrosis, and cardiac function in rats subjected to acute myocardial I/R. The ischemia was induced by ligation of the left anterior descending coronary artery for 30 min and was followed by 3 h of reperfusion. Myocardial malondialdehyde content, infarct size, and collagen volume fraction decreased, while the activity of superoxide dismutase was increased, the expression of VEGF and p-Akt was upregulated, and cardiac function was improved in the HMGB1-treated group when compared with rats subjected to I/R only (all P < 0.05). However, these effects of HMGB1 were abolished by LY294002. The obtained results demonstrate that the cardioprotective effects of intravenous administration of HMGB1 prior to I/R may be mediated by upregulation of myocardial expression of VEGF, which may activate the PI3K/Akt signaling pathway.

Dietary α-Linolenic Acid Counters Cardioprotective Dysfunction in Diabetic Mice: Unconventional PUFA Protection

“…We recently found that post-ischemic AKT levels and phosphorylation are unaltered by IPC or T2D [44], leaving the possibility that phosphorylation patterns during the IPC stimulus and/or initial minutes of reperfusion might be modified with ALA; AKT phosphorylation at these times is linked to I-R outcomes and cardioprotection. Shifts in select inflammatory mediators and VEGF could participate in improved IPC with ALA, while excess TNF-α and HMGB1 are both linked to myocardial injury; TNF-α signaling is also implicated in cardiac preconditioning [131] and HMGB1 may additionally precondition hearts via up-regulating protective VEGF [132], which was augmented by ALA here. Finally, it is also notable that n-3 PUFAs are highly pleiotropic [133], and could influence IPC through cytochrome P450 (e.g., epoxyeicosanoid formation) and arachidonate metabolic pathways [134], inter-related endocannabinoid signaling [135], activation of key transcriptional regulators [136], and/or inhibition of oxidative stress [137].…”

Protective Effects of Dexazoxane on Rat Ferroptosis in Doxorubicin-Induced Cardiomyopathy Through Regulating HMGB1

“…However, the mechanism of DXZ in ferroptosis and DOX-induced rat cardiomyopathy remains largely unknown. High mobility group box 1 (HMGB1) is a ubiquitous and abundant nucleoprotein that plays a key role in many cardiovascular diseases, such as myocardial ischemia/reperfusion injury, myocardial infarction, and heart failure ( 19 ). HMGB1 was also found to be a critical regulator of ferroptosis in many diseases, such as leukemia ( 20 ), acute liver failure ( 21 ), and diabetic nephropathy ( 22 ).…”

Circular RNA Involvement in the Protective Effect of Human Umbilical Cord Mesenchymal Stromal Cell-Derived Extracellular Vesicles Against Hypoxia/Reoxygenation Injury in Cardiac Cells

“…For example, VEGF is an angiogenic growth factor that can stimulate the proliferation, differentiation, and survival of vascular endothelial cells. Several experiments have indicated that VEGF plays a cardio-protective role in myocardial I/R injury (25,26). Further, most of the host genes of the seven validated circRNAs, such as ATXN10, FAM126A, SBDS, PICALM, and FTO, are closely associated with cell survival, cell proliferation, and cell differentiation (27)(28)(29)(30)(31).…”